Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease with both genetic and environmental risk factors that remain incompletely defined. Alterations in the immune regulatory pathways are believed to play an important role in disease pathogenesis, and hundreds of studies have examined the role of potential candidate genes in populations of varying ethnicity and size, often with conflicting results. Hundreds of other candidate genes in immune regulatory pathways appear ripe for study as well, especially since no results have been published regarding their role in SLE. The purpose of this feasibility project is to winnow down our long list of interesting candidates to a few genes worthy of dedicated study in future large proposals. In Specific Aim 1, we will test a cohort of European-American samples consisting of 400 SLE cases and 400 matched controls at 384 SNPs chosen within genes in our candidate lists through the SNP-Gen Core. We have 400 African-American cases and nearly 300 matched controls on hand, and for Specific Aim 2 we will recruit additional African-American patients and controls for testing on the same array. For Specific Aim 3 we utilize on the results of these European-American and African-American cohorts to select genes with promising associations for further study and test them on a confirmation containing both family-based and case-control samples from European-American, African-American, and Hispanic families. For those associations confirmed in this phase, Specific Aim 4 will examine the genes to find functional polymorphisms in cases where the associated SNP does not encode a structural variant or a known regulatory site. These results will enable identification of indisputable genetic risk factors for SLE. The finding of a functional polymorphism associated with SLE would be the perfect springboard for more extensive structure/function studies and the starting point of subsequent applications for funding.